4-hydroxyamphetamine has some limitations to its use as a diagnostic tool. If it is intended as an immediate follow up to another mydriatic drug (cocaine or apraclonidine), then the patient must wait anywhere from a day to a week before 4-hydroxyamphetamine can be administered.[2][3] It also has the tendency to falsely localize lesions. False localization can arise in cases of acute onset; in cases where a postganglionic lesion is present, but the nerve still responds to residual norepinephrine; or in cases in which unrelated nerve damage masks the presence of a preganglionic lesion.[1][2]

Hydroxyamphetamine is a component of two controlled (prescription only), name-brand ophthalmic mydriatics: Paredrine and Paremyd. Paredrine consists of a 1% solution of hydroxyamphetamine hydrobromide[20]:543 while Paremyd consists of a combination of 1% hydroxyamphetamine hydrobromide and 0.25% tropicamide.[21] In the 1990s, the trade name rights, patents, and new drug applications (NDAs) for the two formulations were exchanged among a few different manufacturers after a shortage of the raw material required for their production, which caused both drugs to be indefinitely removed from the market.[22] Around 1997, Akorn, Inc., obtained the rights to both Paredrine and Paremyd,[23] and in 2002, the company reintroduced Paremyd to the market as a fast acting ophthalmic mydriatic agent.[21][24][25]

^4-Hydroxyamphetamine has been shown to be metabolized into 4-hydroxynorephedrine by dopamine beta-hydroxylase (DBH) in vitro and it is presumed to be metabolized similarly in vivo.[10][15] Evidence from studies that measured the effect of serum DBH concentrations on 4-hydroxyamphetamine metabolism in humans suggests that a different enzyme may mediate the conversion of 4-hydroxyamphetamine to 4-hydroxynorephedrine;[15][17] however, other evidence from animal studies suggests that this reaction is catalyzed by DBH in synaptic vesicles within noradrenergic neurons in the brain.[18][19]

^ abcSjoerdsma A, von Studnitz W (April 1963). “Dopamine-beta-oxidase activity in man, using hydroxyamphetamine as substrate”. Br. J. Pharmacol. Chemother. 20: 278–284. doi:10.1111/j.1476-5381.1963.tb01467.x. PMC1703637. PMID13977820. Hydroxyamphetamine was administered orally to five human subjects … Since conversion of hydroxyamphetamine to hydroxynorephedrine occurs in vitro by the action of dopamine-β-oxidase, a simple method is suggested for measuring the activity of this enzyme and the effect of its inhibitors in man. … The lack of effect of administration of neomycin to one patient indicates that the hydroxylation occurs in body tissues. … a major portion of the β-hydroxylation of hydroxyamphetamine occurs in non-adrenal tissue. Unfortunately, at the present time one cannot be completely certain that the hydroxylation of hydroxyamphetamine in vivo is accomplished by the same enzyme which converts dopamine to noradrenaline.

^Badenhorst CP, van der Sluis R, Erasmus E, van Dijk AA (September 2013). “Glycine conjugation: importance in metabolism, the role of glycine N-acyltransferase, and factors that influence interindividual variation”. Expert Opin. Drug Metab. Toxicol. 9 (9): 1139–1153. doi:10.1517/17425255.2013.796929. PMID23650932. Figure 1. Glycine conjugation of benzoic acid. The glycine conjugation pathway consists of two steps. First benzoate is ligated to CoASH to form the high-energy benzoyl-CoA thioester. This reaction is catalyzed by the HXM-A and HXM-B medium-chain acid:CoA ligases and requires energy in the form of ATP. … The benzoyl-CoA is then conjugated to glycine by GLYAT to form hippuric acid, releasing CoASH. In addition to the factors listed in the boxes, the levels of ATP, CoASH, and glycine may influence the overall rate of the glycine conjugation pathway.

^Horwitz D, Alexander RW, Lovenberg W, Keiser HR (May 1973). “Human serum dopamine-β-hydroxylase. Relationship to hypertension and sympathetic activity”. Circ. Res. 32 (5): 594–599. doi:10.1161/01.RES.32.5.594. PMID4713201. The biologic significance of the different levels of serum DβH activity was studied in two ways. First, in vivo ability to β-hydroxylate the synthetic substrate hydroxyamphetamine was compared in two subjects with low serum DβH activity and two subjects with average activity. … In one study, hydroxyamphetamine (Paredrine), a synthetic substrate for DβH, was administered to subjects with either low or average levels of serum DβH activity. The percent of the drug hydroxylated to hydroxynorephedrine was comparable in all subjects (6.5-9.62) (Table 3).

^Freeman JJ, Sulser F (December 1974). “Formation of p-hydroxynorephedrine in brain following intraventricular administration of p-hydroxyamphetamine”. Neuropharmacology. 13 (12): 1187–1190. doi:10.1016/0028-3908(74)90069-0. PMID4457764. In species where aromatic hydroxylation of amphetamine is the major metabolic pathway, p-hydroxyamphetamine (POH) and p-hydroxynorephedrine (PHN) may contribute to the pharmacological profile of the parent drug. … The location of the p-hydroxylation and β-hydroxylation reactions is important in species where aromatic hydroxylation of amphetamine is the predominant pathway of metabolism. Following systemic administration of amphetamine to rats, POH has been found in urine and in plasma.The observed lack of a significant accumulation of PHN in brain following the intraventricular administration of (+)-amphetamine and the formation of appreciable amounts of PHN from (+)-POH in brain tissue in vivo supports the view that the aromatic hydroxylation of amphetamine following its systemic administration occurs predominantly in the periphery, and that POH is then transported through the blood-brain barrier, taken up by noradrenergic neurones in brain where (+)-POH is converted in the storage vesicles by dopamine β-hydroxylase to PHN.